The biological activity and the possible physiological role of Gamma-MSH peptides, which share a common precursor both in pituitary and brain with endorphins and ACTH-MSH like peptides, has been investigated. We have found that the peptide Gamma1-MSH, which is the endogenous amidated form of Gamma-MSH, has a biological profile which resemble that of an opiate agonist. In fact, we found that Gamma1-MSH inhibited the electrically induced contractions of guinea pig ileum myenteric plexus-longitudinal muscle. This effect was reversed by naloxone. Furthermore Gamma1-MSH potentiated the effect of beta-endorphin and leu-enkephalin in this muscle preparation. In rat brain membrane, Gamma1-MSH specifically displaced 3H-dihydromorphine, 3H-ethylketocycloazocine and 3H-D-Ala2-D-Leu5-enkephalin binding with IC-50 of around 10-7M. Moreover the opiate agonistic activity of Gamma1-MSH can be effectively antagonized by ACTH (1-24), Gamma-MSH and ACTH(4-10). These results could indicate that Gamma1-MSH may have a role as synergistic modulator of endorphinergic transmission and ACTH-MSH may in contrast, have modulating effect on this transmission by antagonizing beta-endorphin or Gamma1-MSH opioid-like activity.